Our aim is to define the host and bacterial factors that characterize the clinical and microbiologic latency which distinguish human tuberculosis. We hypothesize that in human tuberculosis, persistent/latent infection is associated with a different immune response than active chronic disease. For Mycobacterium tuberculosis to survive in the face of these varying host immune responses, it must alter its physiology through differential changes in gene expression. Thus a particular clinical state associated with a specific state of immunity will elicit a corresponding profile of genes expressed by the infecting organism (""""""""molecular mirror""""""""). We will utilize M. tuberculosis infected lung tissue obtained from surgical resection of TB patients with active disease, or asymptomatic persistent infection, or recurrent disease. These tuberculous lung specimens will be used to characterize the host immune response by histology and immunohistology combined with real time RT-PCR with molecular beacons to quantitate leukocyte gene expression in the lung. Our collaborator, Dr. John McKinney, will use the same tissues to identify the patterns of M. tuberculosis gene expression in each type of disease. In addition, we will use the rabbit model of M. tuberculosis infection to generate animals with either active disease or persistent asymptomatic infection (latency). Rabbits will be infected with clinical strains of M. tuberculosis of differing degrees of virulence to recreate the range of human disease. Tissues from rabbits with each form of the disease will be used to characterize the cellular response to infection in the lung and to elucidate the patterns of M. tuberculosis gene expression associated with either active disease or persistent asymptomatic infection (latency). We will also infect rabbits with M. tuberculosis mutants selected to be defective for persistence in murine models and establish whether these mutants retain their persistence defect in the rabbit model. By combining the results obtained from the rabbit studies and the human studies, we will validate our experimental animal model as a mirror of human disease and use the model to identify the molecular correlates of M. tuberculosis latency.
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